Cannabinoid (CB) was discovered as the main active substance contained in marijuana in 1960 and its main behavior was an activity in the central nervous system bringing about illusion, euphoria, sensory confusion of time and space, and the like by being ingested.
It has been found that a seven times transmembrane G protein bonded cannabinoid type 1 (CBI) receptor exists in the central nervous system such as the brain in 1990, and besides agonists to the receptor take part in the adjustment of a higher-order function of the brain by restrainedly controlling the neurotransmitter discharge with the signal transmission system in the cell such as controlling adenylate cyclase activity, controlling N- and P/Q types Ca 2+ channels, activating voltage gated K+ channel, and activating MAP kinase activity through the receptor, it has been also found that the receptor exists also in peripheral tissues and has minor activities in non-nervous systems such as an anti-inflammatory activity, and the alleviation of hypotonia bulbi and muscular spasm. Further, a cannabinoid type 2 receptor (CB2) was found to be distributed over immune tissues such as the spleen and agonists to this receptor were found to surpress an activation of immunocyte or inflammatory cells to exhibit an immunosuppressive activity, an anti-inflammatory activity and analgesic activity (Non-patent literature 1). From these facts, the application of agonists to the cannabinoid receptors to medicines has become to be examined widely.
As applications as medicines of agonists to the cannabinoid receptors, the medical treatment for an allergic disease of quinolone derivatives (Patent literatures 1, 2, 3, 4, and 5), 3,4-dihydroisoquinoline derivatives (Patent literature 6), pyridone derivatives (Patent literature 7), and further quinolone derivatives (Patent literature 8) have been described. Moreover, an anti-pruritic activity is disclosed in Patent literatures 10 and 11.
Itching is a kind of biological reaction, and peripheral itching and central itching are known. For example, sweet itchs including inflammatory reactions such as an edema, atopic dermatitis, hives, senile xerosis, and contact dermatitis are peripheral itching caused when nerve endings (itching receptors) of sensory nerve fibers existing in the epidermal-dermal junction are activated by a chemical, physical, or electric stimulus and the like. On the other hand, refractory pruritus such as systemic pruritus of a renal failure patient, which is derived from the hemodialysis, is thought to be central itching that is caused by an opioid peptide uniting with the receptor.
Medicines presently used as an anti-pruritus agent include, for example, diphenhydramine and crotamiton. The former is not effective in other itching though it is effective in the edema and hives that histamine took part as an antihistaminic. Moreover, though the latter adds anti-inflammatory activity by adding a steroid drug and is used as ointment for itching of eczema and the like, the action mechanism is uncertain.
By the way, atopic dermatitis is a cutaneous disease being accompanied by very strong pruritus and skin inflammation in the background of the atopic disposition and accompanied by the decrease in the barrier function, and the wax and wane are repeated. At present, as for medicines that soothe the inflammation and the effectiveness is proven, there are only two kinds, that is, steroids for internal use and for external application, and calcineurin inhibitory medicines that are called the immunosuppressive activity agents or immunoregulation agents for external use such as tacrolimus and eridale. However, there are severe faults such as the existence of steroid refractory patients, various systemic and locality side effects, and rebounds in the steroid. Moreover, though the immunoregulation agent for external use, the action mechanism of which is quite different from the steroid for external application, is highly effective especially for exanthemata in the face and the cervical region, it has peculiar skin stimulation and is a taboo for using especially in epidermolysis surface seen in atopic dermatitis and the like, and an advanced specialty and attention are demanded when using it. These medicines to the atopic dermatitis are symptomatic treatment medicines which aim at moderate solution of the symptom, and not those which aim at the treatment going back even the cause (Non-patent literature 2).
On the other hand, itching is understood as a sense which causes the impulse of wonting to scratch, and scratching off, a blow, and the like, which are accompanied by itching, are often the most complicating factors of atopic dermatitis. That is, if pruritus can be controlled, not only itching, which is the most suffering of the patient, can be softened to improve QOL (Quality of life), but also an indirect effect that an exanthema is improved by controlling scratching off can be expected. For these reasons, the development of a safe anti-pruritus agent that enables the loss in quantity or cessation of the symptomatic treatment medicine and is strong and can endure the chronic administration is wated for.
As one mode of such a medicine, a medicine for external application that acts only on the applied region and can avoid the systemic action by the internal use is cited. That is, compared with oral agents that the medicines are obsorbed from an alimentary canal, an endermic liniment for external application becomes possible to absorb the medicine directly from the disorder affected part by the noninvasive zero-order discharge, to avoid the first-pass effect in the liver, to avoid dosage dependent systemic side effects, and to control medicinal concentration in the disorfer affected part for long periods of time, and the merit of the medicine is considered that it can be used safely for cutaneous diseases often seen especially in elderly people, sick people, and infants. In fact, though the steroid drug has a strong anti-inflammatory activity and an anti-pruritic activity that accompanies it, it is not used as an oral medicine except for the remission of extremely severe symptoms. On the one hand, it is well known that the skin has a remarkably strong barrier function for a lot of medicines, so that effective medicines in oral administration are not necessarily effective even in dermal administration.
The present inventors have eagerly made progress in their studies, resulting in finding that the application of a 3-carbamoyl-2-pyridone derivative shown in the following on the skin of the disorder affected part makes the derivative act directly to the cannabinoid receptor existing in the periphery to reveal excellent anti-pruritic activity.
Though pyridone derivatives similar to the said compounds of the present invention are commercially available from Interbioscreen Corp., Interchim Corp., Asinex Corp., and Ambinter Sarl Corp. as reagents, pharmacological activity on these compounds has not described.
(Patent Literature 1)
International Publication No. 99/02499 Pamphlet
(Patent Literature 2)
International Publication No. 00/40562 Pamphlet
(Patent Literature 3)
International Publication No. 2004/103974 Pamphlet
(Patent Literature 4)
International Publication No. 04/103974 Pamphlet
(Patent Literature 5)
International Publication No. 04/104000 Pamphlet
(Patent Literature 6)
International Publication No. 02/10135 Pamphlet
(Patent Literature 7)
International Publication No. 02/053543 Pamphlet
(Patent Literature 8)
International Publication No. 03/061699 Pamphlet
(Patent Literature 9)
International Publication No. 02/065997 Pamphlet
(Patent Literature 10)
International Publication No. 03/035109 Pamphlet
(Patent Literature 11)
International Publication No. 03/070277 Pamphlet
(Non-Patent Literature 1)
Nature, 1993, vol. 365, p. 61-65
(Non-Patent Literature 2)
Japanese dermatology association's atopic dermatitis treatment guideline, 2004 revised edition, “Japanese skin society magazine”, 2004, p. 114-135